Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment
Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment
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DOI：
10.1093/intimm/dxh307
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发表时间：
2005-10-01
影响因子：
4.4
通讯作者：
Kikutani, H
中科院分区：
文献类型：
--
作者：
Kumanogoh, A;Shikina, T;Kikutani, H
B细胞表面上的辅助受体调节B细胞抗原受体（BCR）信号传导;然而，仍不清楚BCR信号如何协调以维持免疫稳态。CD 72是B细胞反应的负调节因子，在其胞质区域内具有基于免疫受体酪氨酸的抑制基序，酪氨酸磷酸酶SHP-1结合这些位点。CD 72的天然配体CD 100/Sema 4D属于脑信号蛋白家族，并诱导SHP-1从CD 72解离，从而关闭CD 72的负信号。在缺乏CD 100的情况下，由于SHP-1与CD 72的组成性结合，BCR信号被显著抑制，导致B细胞低反应性。在这里，我们表明，CD 100通过阻止CD 72与BCR的关联来调节BCR的敏感性，并且这种相互作用是适当的B细胞稳态所必需的。因此，随着CD 100缺陷小鼠年龄的增长，它们积累边缘区B细胞并产生高自身抗体水平和自身免疫。总的来说，我们的研究结果表明，BCR信号的强度是由CD 100与CD 72的相互作用严格调节的，这种相互作用对于维持免疫稳态以及产生适当的免疫应答至关重要。
Co-receptors on the B-cell surface regulate B-cell antigen receptor (BCR) signaling; however, it remains unclear how BCR signals are coordinated to maintain immune homeostasis. CD72, a negative regulator of B-cell responses, has immunoreceptor tyrosine-based inhibitory motifs within its cytoplasmic region, and the tyrosine phosphatase SHP-1 binds these sites. The natural ligand of CD72, CD100/Sema4D, belongs to the semaphorin family and induces the dissociation of SHP-1 from CD72, thereby switching off the negative signals of CD72. In the absence of CD100, BCR signals are significantly suppressed due to the constitutive association of SHP-1 With CD72, resulting in B-cell hyporesponsiveness. Here we show that CD100 regulates the sensitivity of the BCR by preventing the association of the CD72 with BCR, and this interaction is required for proper B-cell homeostasis. Consequently, as CD100-deficient mice age, they accumulate marginal zone B cells and develop high auto-antibody levels and autoimmunity. Collectively, our findings indicate that the strength of BCR signals is strictly tuned by the interaction of CD100 with CD72, and this interaction is essential for maintaining immunological homeostasis as well as generating a proper immune response.